Novel synthesis for thiazolidinedione compounds

ABSTRACT

The present invention provides novel methods for synthesizing PPARγ sparing compounds, e.g., thiazolidinediones, that are useful for preventing and/or treating metabolic disorders such as diabetes, obesity, hypertension, and inflammatory diseases.

CROSS-REFERENCE TO RELATED APPLICATION

This PCT application claims priority to U.S. Application No. 61/325,502,filed on Apr. 19, 2010 and U.S. Application No. 61/327,498, filed onApr. 23, 2010. The entire contents of the aforementioned applicationsare incorporated herein by reference in their entireties.

TECHNICAL FIELD OF THE INVENTION

The present invention provides novel methods for synthesizing PPARγsparing compounds, e.g., thiazolidinediones, that are useful forpreventing and/or treating metabolic disorders such as diabetes,obesity, hypertension, and inflammatory diseases.

BACKGROUND OF THE INVENTION

Over the past several decades, scientists have postulated that PPARγ isthe generally accepted site of action for insulin sensitizingthiazolidinedione compounds.

Peroxisome Proliferator Activated Receptors (PPARs) are members of thenuclear hormone receptor super-family, which are ligand-activatedtranscription factors regulating gene expression. PPARs have beenimplicated in autoimmune diseases and other diseases, i.e., diabetesmellitus, cardiovascular and gastrointestinal disease, and Alzheimer'sdisease.

PPARγ is a key regulator of adipocyte differentiation and lipidmetabolism. PPARγ is also found in other cell types includingfibroblasts, myocytes, breast cells, human bone-marrow precursors, andmacrophages/monocytes. In addition, PPARγ has been shown in macrophagefoam cells in atherosclerotic plaques.

Thiazolidinediones, such as pioglitazone, developed originally for thetreatment of type-2 diabetes, generally exhibit high affinity as PPARγligands. The finding that thiazolidinediones might mediate theirtherapeutic effects through direct interactions with PPARγ helped toestablish the concept that PPARγ is a key regulator of glucose and lipidhomeostasis. However, compounds that involve the activation of PPARγ,such as pioglitazone, also trigger sodium reabsorption and otherunpleasant side effects.

SUMMARY OF THE INVENTION

In general, the invention relates to methods of synthesizing compoundsthat have reduced binding and activation of the nuclear transcriptionfactor PPARγ when compared with high affinity PPARγ ligands such aspioglitazone. These novel methods are scalable for industrial productionand employ safer, more stable, and/or less costly starting materials andprocess conditions.

Compounds exhibiting PPARγ activity induce transcription of genes thatfavor sodium reabsorption. Advantageously, the compounds produced by thesyntheses of this invention have reduced binding or activation of thenuclear transcription factor PPARγ when compared with traditional highaffinity PPARγ ligands (e.g., pioglitazone or rosiglitazone), andtherefore produce fewer or diminished side effects (e.g., reducedaugmentation of sodium reabsorption) that are associated withtraditional high affinity PPARγ ligands, and are therefore more usefulin treating hypertension, diabetes, and inflammatory diseases. Mostspecifically, the reduced PPARγ binding and reduced activity exhibitedby these compounds, as compared with traditional high affinity PPARγligands (e.g., pioglitazone or rosiglitazone), are particularly usefulfor treating hypertension, diabetes, and inflammatory diseases both assingle agents and in combination with other classes of antihypertensiveagents. As hypertension and inflammatory diseases pose major riskfactors in the onset of diabetes and pre-diabetes, these compounds arealso useful for the treatment and prevention of diabetes and otherinflammatory diseases. In fact, compounds synthesized by the presentinvention may induce remission of the symptoms of diabetes in a humanpatient.

One aspect of the present invention provides a novel synthesis forgenerating thiazolidinedione compounds that are useful for the treatmentof metabolic disorders. This synthesis is useful for preparing acompound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein each of R₁ and R₃is independently selected from H, halo, aliphatic, and alkoxy, whereinthe aliphatic or alkoxy is optionally substituted with 1-3 of halo; eachof R′₂ and R₂ are independently selected from —H, halo, hydroxy, oroptionally substituted aliphatic, alkoxy, —O-acyl, —O-aroyl,—O-heteroaroyl, —O(SO₂)NH₂, —O—CH(R_(m))OC(O)R_(n),—O—CH(R_(m))OP(O)(OR_(n))₂—O—P(O)(OR_(n))₂, or

wherein each R_(m) is independently C₁₋₆ alkyl, each R_(n) isindependently C₁₋₁₂ alkyl, C₃₋₈ cycloalkyl, or phenyl, each of which isoptionally substituted; R₂ and R′₂ together form oxo, R₂ and R′₂together form —O(CH₂)_(n)O—, wherein n is 2 or 3, or R₂ and R′₂ togetherform —S(CH₂)_(m)S—, wherein m is 2 or 3; and ring A is phenyl,pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, each of which is optionallysubstituted; comprising the step of reacting a compound of Formula 2A:

wherein X is a leaving group, with a compound of Formula 3A

wherein ring B is selected from

wherein Y₁ is hydrogen or PG_(N) and Y₂ is PG_(O), wherein PG_(N) is anitrogen protecting group and PG_(O) is an oxygen protecting group, toform a compound of Formula 4A; and

when Y₁ is other than hydrogen or when Y₂ is present, deprotecting thecompound of Formula 4A to form a compound of Formula I.

DETAILED DESCRIPTION

The present invention provides novel methods for preparingthiazolidinedione compounds having reduced PPARγ activity.

As used herein, the following definitions shall apply unless otherwiseindicated.

I. DEFINITIONS

For purposes of this invention, the chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75th Ed. Additionally, generalprinciples of organic chemistry are described in “Organic Chemistry”,Thomas Sorrell, University Science Books, Sausalito: 1999, and “March'sAdvanced Organic Chemistry”, 5th Ed., Ed.: Smith, M. B. and March, J.,John Wiley & Sons, New York: 2001, the entire contents of which arehereby incorporated by reference.

As described herein, “protecting group” refers to a moiety orfunctionality that is introduced into a molecule by chemicalmodification of a functional group in order to obtain chemoselectivityin a subsequent chemical reaction. Standard protecting groups areprovided in Wuts and Greene: “Greene's Protective Groups in OrganicSynthesis” 4th Ed, Wuts, P.G.M. and Greene, T. W., Wiley-Interscience,New York: 2006.

As described herein, compounds of the invention may optionally besubstituted with one or more moieties, such as are illustrated generallyabove, or as exemplified by particular classes, subclasses, and speciesof the invention.

As used herein, the term “hydroxyl” or “hydroxy” refers to an —OHmoiety.

As used herein the term “aliphatic” encompasses the terms alkyl,alkenyl, alkynyl, each of which being optionally substituted as setforth below.

As used herein, an “alkyl” group refers to a saturated aliphatichydrocarbon group containing 1-12 (e.g., 1-8, 1-6, or 1-4) carbon atoms.An alkyl group can be straight or branched. Examples of alkyl groupsinclude, but are not limited to, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, or2-ethylhexyl. An alkyl group can be substituted (i.e., optionallysubstituted) with one or more substituents such as halo, phospho,cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], heterocycloaliphatic[e.g., heterocycloalkyl or heterocycloalkenyl], aryl, heteroaryl,alkoxy, aroyl, heteroaroyl, acyl [e.g., (aliphatic)carbonyl,(cycloaliphatic)carbonyl, or (heterocycloaliphatic)carbonyl], nitro,cyano, amido [e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino,aralkylcarbonylamino, (heterocycloalkyl)carbonylamino,(heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino,heteroaralkylcarbonylamino alkylaminocarbonyl, cycloalkylaminocarbonyl,heterocycloalkylaminocarbonyl, arylaminocarbonyl, orheteroarylaminocarbonyl], amino [e.g., aliphaticamino,cycloaliphaticamino, or heterocycloaliphaticamino], sulfonyl [e.g.,aliphatic-SO₂—], sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl,sulfamide, oxo, carboxy, carbamoyl, cycloaliphaticoxy,heterocycloaliphaticoxy, aryloxy, heteroaryloxy, aralkyloxy,heteroarylalkoxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxy. Withoutlimitation, some examples of substituted alkyls include carboxyalkyl(such as HOOC-alkyl, alkoxycarbonylalkyl, and alkylcarbonyloxyalkyl),cyanoalkyl, hydroxyalkyl, alkoxyalkyl, acylalkyl, aralkyl,(alkoxyaryl)alkyl, (sulfonylamino)alkyl (such as(alkyl-SO₂-amino)alkyl), aminoalkyl, amidoalkyl, (cycloaliphatic)alkyl,or haloalkyl.

As used herein, an “alkenyl” group refers to an aliphatic carbon groupthat contains 2-8 (e.g., 2-12, 2-6, or 2-4) carbon atoms and at leastone double bond. Like an alkyl group, an alkenyl group can be straightor branched. Examples of an alkenyl group include, but are not limitedto allyl, isoprenyl, 2-butenyl, and 2-hexenyl. An alkenyl group can beoptionally substituted with one or more substituents such as halo,phospho, cycloaliphatic [e.g., cycloalkyl or cycloalkenyl],heterocycloaliphatic [e.g., heterocycloalkyl or heterocycloalkenyl],aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [e.g.,(aliphatic)carbonyl, (cycloaliphatic)carbonyl, or(heterocycloaliphatic)carbonyl], nitro, cyano, amido [e.g.,(cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino,(heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino,heteroarylcarbonylamino, heteroaralkylcarbonylamino alkylaminocarbonyl,cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl,arylaminocarbonyl, or heteroarylaminocarbonyl], amino [e.g.,aliphaticamino, cycloaliphaticamino, heterocycloaliphaticamino, oraliphaticsulfonylamino], sulfonyl [e.g., alkyl-SO₂—,cycloaliphatic-SO₂—, or aryl-SO₂—], sulfinyl, sulfanyl, sulfoxy, urea,thiourea, sulfamoyl, sulfamide, oxo, carboxy, carbamoyl,cycloaliphaticoxy, heterocycloaliphaticoxy, aryloxy, heteroaryloxy,aralkyloxy, heteroaralkoxy, alkoxycarbonyl, alkylcarbonyloxy, orhydroxy. Without limitation, some examples of substituted alkenylsinclude cyanoalkenyl, alkoxyalkenyl, acylalkenyl, hydroxyalkenyl,aralkenyl, (alkoxyaryl)alkenyl, (sulfonylamino)alkenyl (such as(alkyl-SO₂-amino)alkenyl), aminoalkenyl, amidoalkenyl,(cycloaliphatic)alkenyl, or haloalkenyl.

As used herein, an “alkynyl” group refers to an aliphatic carbon groupthat contains 2-8 (e.g., 2-12, 2-6, or 2-4) carbon atoms and has atleast one triple bond. An alkynyl group can be straight or branched.Examples of an alkynyl group include, but are not limited to, propargyland butynyl. An alkynyl group can be optionally substituted with one ormore substituents such as aroyl, heteroaroyl, alkoxy, cycloalkyloxy,heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, nitro, carboxy,cyano, halo, hydroxy, sulfo, mercapto, sulfanyl [e.g., aliphaticsulfanylor cycloaliphaticsulfanyl], sulfinyl [e.g., aliphaticsulfinyl orcycloaliphaticsulfinyl], sulfonyl [e.g., aliphatic-SO₂—,aliphaticamino-SO₂—, or cycloaliphatic-SO₂—], amido [e.g.,aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino,cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl,cycloalkylcarbonylamino, arylaminocarbonyl, arylcarbonylamino,aralkylcarbonylamino, (heterocycloalkyl)carbonylamino,(cycloalkylalkyl)carbonylamino, heteroaralkylcarbonylamino,heteroarylcarbonylamino or heteroarylaminocarbonyl], urea, thiourea,sulfamoyl, sulfamide, alkoxycarbonyl, allylcarbonyloxy, cycloaliphatic,heterocycloaliphatic, aryl, heteroaryl, acyl [e.g.,(cycloaliphatic)carbonyl or (heterocycloaliphatic)carbonyl], amino[e.g., aliphaticamino], sulfoxy, oxo, carboxy, carbamoyl,(cycloaliphatic)oxy, (heterocycloaliphatic)oxy, or (heteroaryl)alkoxy.

As used herein, an “amido” encompasses both “aminocarbonyl” and“carbonylamino”. These terms when used alone or in connection withanother group refer to an amido group such as —N(R^(X))—C(O)—R^(Y) or—C(O)—N(R^(X))₂, when used terminally, and —C(O)—N(R^(X))— or—N(R^(X))—C(O)— when used internally, wherein R^(X) and R^(Y) can bealiphatic, cycloaliphatic, aryl, araliphatic, heterocycloaliphatic,heteroaryl or heteroaraliphatic. Examples of amido groups includealkylamido (such as alkylcarbonylamino or alkylaminocarbonyl),(heterocycloaliphatic)amido, (heteroaralkyl)amido, (heteroaryl)amido,(heterocycloalkyl)alkylamido, arylamido, aralkylamido,(cycloalkyl)alkylamido, or cycloalkylamido.

As used herein, an “amino” group refers to —NR^(X)R^(Y) wherein each ofR^(X) and R^(Y) is independently hydrogen, aliphatic, cycloaliphatic,(cycloaliphatic)aliphatic, aryl, araliphatic, heterocycloaliphatic,(heterocycloaliphatic)aliphatic, heteroaryl, carboxy, sulfanyl,sulfinyl, sulfonyl, (aliphatic)carbonyl, (cycloaliphatic)carbonyl,((cycloaliphatic)aliphatic)carbonyl, arylcarbonyl,(araliphatic)carbonyl, (heterocycloaliphatic)carbonyl,((heterocycloaliphatic)aliphatic)carbonyl, (heteroaryl)carbonyl, orheteroaraliphatic)carbonyl, each of which being defined herein and beingoptionally substituted. Examples of amino groups include alkylamino,dialkylamino, or arylamino. When the term “amino” is not the terminalgroup (e.g., alkylcarbonylamino), it is represented by —NR^(X)—, whereR^(X) has the same meaning as defined above.

As used herein, an “aryl” group used alone or as part of a larger moietyas in “aralkyl”, “aralkoxy”, or “aryloxyalkyl” refers to monocyclic(e.g., phenyl); bicyclic (e.g., indenyl, naphthalenyl,tetrahydronaphthyl, tetrahydroindenyl); and tricyclic (e.g., fluorenyltetrahydrofluorenyl, or tetrahydroanthracenyl, anthracenyl) ring systemsin which the monocyclic ring system is aromatic or at least one of therings in a bicyclic or tricyclic ring system is aromatic. The bicyclicand tricyclic groups include benzofused 2-3 membered carbocyclic rings.For example, a benzofused group includes phenyl fused with two or moreC₄₋₈ carbocyclic moieties. An aryl is optionally substituted with one ormore substituents including aliphatic [e.g., alkyl, alkenyl, oralkynyl]; cycloaliphatic; (cycloaliphatic)aliphatic;heterocycloaliphatic; (heterocycloaliphatic)aliphatic; aryl; heteroaryl;alkoxy; (cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy;heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl;heteroaroyl; amino; oxo (on a non-aromatic carbocyclic ring of abenzofused bicyclic or tricyclic aryl); nitro; carboxy; amido; acyl[e.g., (aliphatic)carbonyl; (cycloaliphatic)carbonyl;((cycloaliphatic)aliphatic)carbonyl; (araliphatic)carbonyl;(heterocycloaliphatic)carbonyl;((heterocycloaliphatic)aliphatic)carbonyl; or(heteroaraliphatic)carbonyl]; sulfonyl [e.g., aliphatic-SO₂— oramino-SO₂—]; sulfinyl [e.g., aliphatic-S(O)— or cycloaliphatic-S(O)—];sulfanyl [e.g., aliphatic-S—]; cyano; halo; hydroxy; mercapto; sulfoxy;urea; thiourea; sulfamoyl; sulfamide; or carbamoyl. Alternatively, anaryl can be unsubstituted.

Non-limiting examples of substituted aryls include haloaryl [e.g.,mono-, di (such as p,m-dihaloaryl), and (trihalo)aryl]; (carboxy)aryl[e.g., (alkoxycarbonyl)aryl, ((aralkyl)carbonyloxy)aryl, and(alkoxycarbonyl)aryl]; (amido)aryl [e.g., (aminocarbonyl)aryl,(((alkylamino)alkyl)aminocarbonyl)aryl, (alkylcarbonyl)aminoaryl,(arylaminocarbonyl)aryl, and (((heteroaryl)amino)carbonyl)aryl];aminoaryl [e.g., ((alkylsulfonyl)amino)aryl or ((dialkyl)amino)aryl];(cyanoalkyl)aryl; (alkoxy)aryl; (sulfamoyl)aryl [e.g.,(aminosulfonyl)aryl]; (alkylsulfonyl)aryl; (cyano)aryl;(hydroxyalkyl)aryl; ((alkoxy)alkyl)aryl; (hydroxy)aryl,((carboxy)alkyl)aryl; (((dialkyl)amino)alkyl)aryl; (nitroalkyl)aryl;(((alkylsulfonyl)amino)alkyl)aryl; ((heterocycloaliphatic)carbonyl)aryl;((alkylsulfonyl)alkyl)aryl; (cyanoalkyl)aryl; (hydroxyalkyl)aryl;(alkylcarbonyl)aryl; alkylaryl; (trihaloalkyl)aryl;p-amino-m-alkoxycarbonylaryl; p-amino-m-cyanoaryl; p-halo-m-aminoaryl;or (m-(heterocycloaliphatic)-o-(alkyl))aryl.

As used herein, an “araliphatic” such as an “aralkyl” group refers to analiphatic group (e.g., a C₁₋₄ alkyl group) that is substituted with anaryl group. “Aliphatic,” “alkyl,” and “aryl” are defined herein. Anexample of an araliphatic such as an aralkyl group is benzyl.

As used herein, an “aralkyl” group refers to an alkyl group (e.g., aC₁₋₄ alkyl group) that is substituted with an aryl group. Both “alkyl”and “aryl” have been defined above. An example of an aralkyl group isbenzyl. An aralkyl is optionally substituted with one or moresubstituents such as aliphatic [e.g., alkyl, alkenyl, or alkynyl,including carboxyalkyl, hydroxyalkyl, or haloalkyl such astrifluoromethyl], cycloaliphatic [e.g., cycloalkyl or cycloalkenyl],(cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl,heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy,heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro,carboxy, alkoxycarbonyl, alkylcarbonyloxy, amido [e.g., aminocarbonyl,alkylcarbonylamino, cycloalkylcarbonylamino,(cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino,(heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino,heteroarylcarbonylamino, or heteroaralkylcarbonylamino], cyano, halo,hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea,sulfamoyl, sulfamide, oxo, or carbamoyl.

As used herein, a “bicyclic ring system” includes 8-12 (e.g., 9, 10, or11) membered structures that form two rings, wherein the two rings haveat least one atom in common (e.g., 2 atoms in common). Bicyclic ringsystems include bicycloaliphatics (e.g., bicycloalkyl orbicycloalkenyl), bicycloheteroaliphatics, bicyclic aryls, and bicyclicheteroaryls.

As used herein, a “cycloaliphatic” group encompasses a “cycloalkyl”group and a “cycloalkenyl” group, each of which being optionallysubstituted as set forth below.

As used herein, a “cycloalkyl” group refers to a saturated carbocyclicmono- or bicyclic (fused or bridged) ring of 3-10 (e.g., 5-10) carbonatoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, cubyl,octahydro-indenyl, decahydro-naphthyl, bicyclo[3.2.1]octyl,bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2.]decyl,bicyclo[2.2.2]octyl, adamantyl, or((aminocarbonyl)cycloalkyl)cycloalkyl.

A “cycloalkenyl” group, as used herein, refers to a non-aromaticcarbocyclic ring of 3-10 (e.g., 4-8) carbon atoms having one or moredouble bonds. Examples of cycloalkenyl groups include cyclopentenyl,1,4-cyclohexa-di-enyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl,octahydro-naphthyl, cyclohexenyl, cyclopentenyl, bicyclo[2.2.2]octenyl,or bicyclo[3.3.1]nonenyl.

A cycloalkyl or cycloalkenyl group can be optionally substituted withone or more substituents such as phosphor, aliphatic [e.g., alkyl,alkenyl, or alkynyl], cycloaliphatic, (cycloaliphatic) aliphatic,heterocycloaliphatic, (heterocycloaliphatic) aliphatic, aryl,heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy,aryloxy, heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl,heteroaroyl, amino, amido [e.g., (aliphatic)carbonylamino,(cycloaliphatic)carbonylamino, ((cycloaliphatic)aliphatic)carbonylamino,(aryl)carbonylamino, (araliphatic)carbonylamino,(heterocycloaliphatic)carbonylamino,((heterocycloaliphatic)aliphatic)carbonylamino,(heteroaryl)carbonylamino, or (heteroaraliphatic)carbonylamino], nitro,carboxy [e.g., HOOC—, alkoxycarbonyl, or alkylcarbonyloxy], acyl [e.g.,(cycloaliphatic)carbonyl, ((cycloaliphatic) aliphatic)carbonyl,(araliphatic)carbonyl, (heterocycloaliphatic)carbonyl,((heterocycloaliphatic)aliphatic)carbonyl, or(heteroaraliphatic)carbonyl], cyano, halo, hydroxy, mercapto, sulfonyl[e.g., alkyl-SO₂— and aryl-SO₂—], sulfinyl [e.g., alkyl-S(O)—], sulfanyl[e.g., alkyl-S—], sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, orcarbamoyl.

As used herein, the term “heterocycloaliphatic” encompassesheterocycloalkyl groups and heterocycloalkenyl groups, each of whichbeing optionally substituted as set forth below.

As used herein, a “heterocycloalkyl” group refers to a 3-10 memberedmono- or bicylic (fused or bridged) (e.g., 5- to 10-membered mono- orbicyclic) saturated ring structure, in which one or more of the ringatoms is a heteroatom (e.g., N, O, S, or combinations thereof). Examplesof a heterocycloalkyl group include piperidyl, piperazyl, azetidinyl,tetrahydropyranyl, tetrahydrofuryl, 1,4-dioxolanyl, 1,4-dithianyl,1,3-dioxolanyl, oxazolidyl, isoxazolidyl, morpholinyl, thiomorpholyl,octahydrobenzofuryl, octahydrochromenyl, octahydrothiochromenyl,octahydroindolyl, octahydropyrindinyl, decahydroquinolinyl,octahydrobenzo[b]thiopheneyl, 2-oxa-bicyclo[2.2.2]octyl,1-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, and2,6-dioxa-tricyclo[3.3.1.0^(3,7)]nonyl. A monocyclic heterocycloalkylgroup can be fused with a phenyl moiety to form structures, such astetrahydroisoquinoline, which would be categorized as heteroaryls.

A “heterocycloalkenyl” group, as used herein, refers to a mono- orbicylic (e.g., 5- to 10-membered mono- or bicyclic) non-aromatic ringstructure having one or more double bonds, and wherein one or more ofthe ring atoms is a heteroatom (e.g., N, O, or S). Monocyclic andbicyclic heterocycloaliphatics are numbered according to standardchemical nomenclature.

A heterocycloalkyl or heterocycloalkenyl group can be optionallysubstituted with one or more substituents such as phosphor, aliphatic[e.g., alkyl, alkenyl, or alkynyl], cycloaliphatic,(cycloaliphatic)aliphatic, heterocycloaliphatic,(heterocycloaliphatic)aliphatic, aryl, heteroaryl, alkoxy,(cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy, heteroaryloxy,(araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino,amido [e.g., (aliphatic)carbonylamino, (cycloaliphatic)carbonylamino,((cycloaliphatic) aliphatic)carbonylamino, (aryl)carbonylamino,(araliphatic)carbonylamino, (heterocycloaliphatic)carbonylamino,((heterocycloaliphatic) aliphatic)carbonylamino,(heteroaryl)carbonylamino, or (heteroaraliphatic)carbonylamina nitro,carboxy [e.g., HOOC—, alkoxycarbonyl, or alkylcarbonyloxy], acyl [e.g.,(cycloaliphatic)carbonyl, ((cycloaliphatic) aliphatic)carbonyl,(araliphatic)carbonyl, (heterocycloaliphatic)carbonyl,((heterocycloaliphatic)aliphatic)carbonyl, or(heteroaraliphatic)carbonyl], nitro, cyano, halo, hydroxy, mercapto,sulfonyl [e.g., alkylsulfonyl or arylsulfonyl], sulfinyl [e.g.,alkylsulfinyl], sulfanyl [e.g., alkylsulfanyl], sulfoxy, urea, thiourea,sulfamoyl, sulfamide, oxo, or carbamoyl.

A “heteroaryl” group, as used herein, refers to a monocyclic, bicyclic,or tricyclic ring system having 4 to 15 ring atoms wherein one or moreof the ring atoms is a heteroatom (e.g., N, O, S, or combinationsthereof) and in which the monocyclic ring system is aromatic or at leastone of the rings in the bicyclic or tricyclic ring systems is aromatic.A heteroaryl group includes a benzofused ring system having 2 to 3rings. For example, a benzofused group includes benzo fused with one ortwo 4 to 8 membered heterocycloaliphatic moieties (e.g., indolizyl,indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl,benzo[b]thiophenyl, quinolinyl, or isoquinolinyl). Some examples ofheteroaryl are pyridyl, 1H-indazolyl, furyl, pyrrolyl, thienyl,thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolinyl,benzthiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole,benzo[1,3]dioxole, benzo[b]furyl, benzo[b]thiophenyl, indazolyl,benzimidazolyl, benzthiazolyl, puryl, cinnolyl, quinolyl, quinazolyl,cinnolyl, phthalazyl, quinazolyl, quinoxalyl, isoquinolyl,4H-quinolizyl, benzo-1,2,5-thiadiazolyl, or 1,8-naphthyridyl.

Without limitation, monocyclic heteroaryls include furyl, thiophenyl,2H-pyrrolyl, pyrrolyl, oxazolyl, thazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4-H-pranyl,pyridyl, pyridazyl, pyrimidyl, pyrazolyl, pyrazyl, or 1,3,5-triazyl.Monocyclic heteroaryls are numbered according to standard chemicalnomenclature.

Without limitation, bicyclic heteroaryls include indolizyl, indolyl,isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl, benzo[b]thiophenyl,quinolinyl, isoquinolinyl, indolizyl, isoindolyl, indolyl,benzo[b]furyl, bexo[b]thiophenyl, indazolyl, benzimidazyl,benzthiazolyl, purinyl, 4H-quinolizyl, quinolyl, isoquinolyl, cinnolyl,phthalazyl, quinazolyl, quinoxalyl, 1,8-naphthyridyl, or pteridyl.Bicyclic heteroaryls are numbered according to standard chemicalnomenclature.

A heteroaryl is optionally substituted with one or more substituentssuch as aliphatic [e.g., alkyl, alkenyl, or alkynyl]; cycloaliphatic;(cycloaliphatic)aliphatic; heterocycloaliphatic;(heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy;(cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy; heteroaryloxy;(araliphatic)oxy; (heteroaraliphatic)oxy; aroyl; heteroaroyl; amino; oxo(on a non-aromatic carbocyclic or heterocyclic ring of a bicyclic ortricyclic heteroaryl); carboxy; amido; acyl [e.g., aliphaticcarbonyl;(cycloaliphatic)carbonyl; ((cycloaliphatic)aliphatic)carbonyl;(araliphatic)carbonyl; (heterocycloaliphatic)carbonyl;((heterocycloaliphatic)aliphatic)carbonyl; or(heteroaraliphatic)carbonyl]; sulfonyl [e.g., aliphaticsulfonyl oraminosulfonyl]; sulfinyl [e.g., aliphaticsulfinyl]; sulfanyl [e.g.,aliphaticsulfanyl]; nitro; cyano; halo; hydroxy; mercapto; sulfoxy;urea; thiourea; sulfamoyl; sulfamide; or carbamoyl. Alternatively, aheteroaryl can be unsubstituted.

Non-limiting examples of substituted heteroaryls include(halo)heteroaryl [e.g., mono- and di-(halo)heteroaryl];(carboxy)heteroaryl [e.g., (alkoxycarbonyl)heteroaryl]; cyanoheteroaryl;aminoheteroaryl [e.g., ((alkylsulfonyl)amino)heteroaryl and((dialkyl)amino)heteroaryl]; (amido)heteroaryl [e.g.,aminocarbonylheteroaryl, ((alkylcarbonyl)amino)heteroaryl,((((alkyl)amino)alkyl)aminocarbonyl)heteroaryl,(((heteroaryl)amino)carbonyl)heteroaryl,((heterocycloaliphatic)carbonyl)heteroaryl, and((alkylcarbonyl)amino)heteroaryl]; (cyanoalkyl)heteroaryl;(alkoxy)heteroaryl; (sulfamoyl)heteroaryl [e.g.,(aminosulfonyl)heteroaryl]; (sulfonyl)heteroaryl [e.g.,(alkylsulfonyl)heteroaryl]; (hydroxyalkyl)heteroaryl;(alkoxyalkyl)heteroaryl; (hydroxy)heteroaryl;((carboxy)alkyl)heteroaryl; (((dialkyl)amino)alkyl]heteroaryl;(heterocycloaliphatic)heteroaryl; (cycloaliphatic)heteroaryl;(nitroalkyl)heteroaryl; (((alkylsulfonyl)amino)alkyl)heteroaryl;((alkylsulfonyl)alkyl)heteroaryl; (cyanoalkyl)heteroaryl;(acyl)heteroaryl [e.g., (alkylcarbonyl)heteroaryl]; (alkyl)heteroaryl;or (haloalkyl)heteroaryl [e.g., trihaloalkylheteroaryl].

A “heteroaraliphatic (such as a heteroaralkyl group) as used herein,refers to an aliphatic group (e.g., a C₁₋₄ alkyl group) that issubstituted with a heteroaryl group. “Aliphatic,” “alkyl,” and“heteroaryl” have been defined above.

A “heteroaralkyl” group, as used herein, refers to an alkyl group (e.g.,a C₁₋₄ alkyl group) that is substituted with a heteroaryl group. Both“alkyl” and “heteroaryl” have been defined above. A heteroaralkyl isoptionally substituted with one or more substituents such as alkyl(including carboxyalkyl, hydroxyalkyl, and haloalkyl such astrifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy,cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy,heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl,alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino,cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino,arylcarbonylamino, aralkylcarbonylamino,(heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino,heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo,hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea,sulfamoyl, sulfamide, oxo, or carbamoyl.

As used herein, “cyclic moiety” and “cyclic group” refer to mono-, bi-,and tri-cyclic ring systems including cycloaliphatic,heterocycloaliphatic, aryl, or heteroaryl, each of which has beenpreviously defined.

As used herein, a “bridged bicyclic ring system” refers to a bicyclicheterocyclicalipahtic ring system or bicyclic cycloaliphatic ring systemin which the rings are bridged. Examples of bridged bicyclic ringsystems include, but are not limited to, adamantanyl, norbornanyl,bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl,bicyclo[3.3.2]decyl, 2-oxabicyclo[2.2.2]octyl, 1-azabicyclo[2.2.2]octyl,3-azabicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.0^(3,7)]nonyl. Abridged bicyclic ring system can be optionally substituted with one ormore substituents such as alkyl (including carboxyalkyl, hydroxyalkyl,and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl,(cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl,heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy,heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro,carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl,alkylcarbonylamino, cycloalkylcarbonylamino,(cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino,(heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino,heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo,hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea,sulfamoyl, sulfamide, oxo, or carbamoyl.

As used herein, an “acyl” group refers to a formyl group or R^(X)—C(O)—(such as alkyl-C(O)—, also referred to as “alkylcarbonyl”) where R^(X)and “alkyl” have been defined previously. Acetyl and pivaloyl areexamples of acyl groups.

As used herein, an “aroyl” or “heteroaroyl” refers to an aryl-C(O)— or aheteroaryl-C(O)—. The aryl and heteroaryl portion of the aroyl orheteroaroyl is optionally substituted as previously defined.

As used herein, an “alkoxy” group refers to an alkyl-O— group where“alkyl” has been defined previously.

As used herein, a “carbamoyl” group refers to a group having thestructure —O—CO—NR^(X)R^(Y) or —NR^(X)—CO—O—R^(Z), wherein R^(X) andR^(Y) have been defined above and R^(Z) can be aliphatic, aryl,araliphatic, heterocycloaliphatic, heteroaryl, or heteroaraliphatic.

As used herein, a “carboxy” group refers to —COOH, —COOR^(X), —OC(O)H,—OC(O)R^(X), when used as a terminal group; or —OC(O)— or —C(O)O— whenused as an internal group.

As used herein, a “haloaliphatic” group refers to an aliphatic groupsubstituted with 1-3 halogen. For instance, the term haloalkyl includesthe group —CF₃.

As used herein, a “mercapto” group refers to —SH.

As used herein, a “sulfo” group refers to —SO₃H or —SO₃R^(X) when usedterminally or —S(O)₃— when used internally.

As used herein, a “sulfamide” group refers to the structure—NR^(X)—S(O)₂—NR^(Y)R^(Z) when used terminally and —NR^(X)—S(O)₂—NR^(Y)—when used internally, wherein R^(X), R^(Y), and R^(Z) have been definedabove.

As used herein, a “sulfamoyl” group refers to the structure—O—S(O)₂—NR^(Y)R^(Z) wherein R^(Y) and R^(Z) have been defined above.

As used herein, a “sulfonamide” group refers to the structure—S(O)₂—NR^(X)R^(Y) or —NR^(X)—S(O)₂—R^(Z) when used terminally; or—S(O)₂—NR^(X)— or —NR^(X)—S(O)₂— when used internally, wherein R^(X),R^(Y), and R^(Z) are defined above.

As used herein a “sulfanyl” group refers to —S—R^(X) when usedterminally and —S— when used internally, wherein R^(X) has been definedabove. Examples of sulfanyls include aliphatic-S—, cycloaliphatic-S—,aryl-S—, or the like.

As used herein a “sulfinyl” group refers to —S(O)—R^(X) when usedterminally and —S(O)— when used internally, wherein R^(X) has beendefined above. Exemplary sulfinyl groups include aliphatic-S(O)—,aryl-S(O)—, (cycloaliphatic(aliphatic))-S(O)—, cycloalkyl-S(O)—,heterocycloaliphatic-S(O)—, heteroaryl-S(O)—, or the like.

As used herein, a “sulfonyl” group refers to —S(O)₂—R^(X) when usedterminally and —S(O)₂— when used internally, wherein R^(X) has beendefined above. Exemplary sulfonyl groups include aliphatic-S(O)₂—,aryl-S(O)₂—, (cycloaliphatic(aliphatic))-S(O)₂—, cycloaliphatic-S(O)₂—,heterocycloaliphatic-S(O)₂—, heteroaryl-S(O)₂—,(cycloaliphatic(amido(aliphatic)))-S(O)₂— or the like.

As used herein, a “sulfoxy” group refers to —O—SO—R^(X) or —SO—O—R^(X),when used terminally and —O—S(O)— or —S(O)—O— when used internally,where R^(X) has been defined above.

As used herein, a “halogen” or “halo” group refers to fluorine,chlorine, bromine or iodine.

As used herein, an “alkoxycarbonyl,” which is encompassed by the termcarboxy, used alone or in connection with another group refers to agroup such as alkyl-O—C(O)—.

As used herein, an “alkoxyalkyl” refers to an alkyl group such asalkyl-O-alkyl-, wherein alkyl has been defined above.

As used herein, a “carbonyl” refer to —C(O)—.

As used herein, an “oxo” refers to =0.

As used herein, the term “phospho” refers to phosphinates andphosphonates. Examples of phosphinates and phosphonates include—P(O)(R^(P))₂, wherein R^(P) is aliphatic, alkoxy, aryloxy,heteroaryloxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy aryl,heteroaryl, cycloaliphatic or amino.

As used herein, an “aminoalkyl” refers to the structure(R^(X))₂N-alkyl-.

As used herein, a “cyanoalkyl” refers to the structure (NC)-alkyl-.

As used herein, a “urea” group refers to the structure—NR^(X)—CO—NR^(Y)R^(Z) and a “thiourea” group refers to the structure—NR^(X)—CS—NR^(Y)R^(Z) when used terminally and —NR^(X)—CO—NR^(Y)— or—NR^(X)—CS—NR^(Y)— when used internally, wherein R^(X), R^(Y), and R^(Z)have been defined above.

As used herein, a “guanidine” group refers to the structure—N═C(N(R^(X)R^(Y)))N(R^(X)R^(Y)) or —NR^(X)—C(═NR^(X))NR^(X)R^(Y)wherein R^(X) and R^(Y) have been defined above.

As used herein, the term “amidino” group refers to the structure—C═(NR^(X))N(R^(X)R^(Y)) wherein R^(X) and R^(Y) have been definedabove.

In general, the term “vicinal” refers to the placement of substituentson a group that includes two or more carbon atoms, wherein thesubstituents are attached to adjacent carbon atoms.

In general, the term “geminal” refers to the placement of substituentson a group that includes two or more carbon atoms, wherein thesubstituents are attached to the same carbon atom.

The terms “terminally” and “internally” refer to the location of a groupwithin a substituent. A group is terminal when the group is present atthe end of the substituent not further bonded to the rest of thechemical structure. Carboxyalkyl, i.e., R^(X)O(O)C-alkyl is an exampleof a carboxy group used terminally. A group is internal when the groupis present in the middle of a substituent of the chemical structure.Alkylcarboxy (e.g., alkyl-C(O)O— or alkyl-OC(O)—) and alkylcarboxyaryl(e.g., alkyl-C(O)O-aryl- or alkyl-O(CO)-aryl-) are examples of carboxygroups used internally.

As used herein, an “aliphatic chain” refers to a branched or straightaliphatic group (e.g., alkyl groups, alkenyl groups, or alkynyl groups).A straight aliphatic chain has the structure —[CH₂]_(v)—, where v is1-12. A branched aliphatic chain is a straight aliphatic chain that issubstituted with one or more aliphatic groups. A branched aliphaticchain has the structure —[CQQ]_(v)- where Q is independently a hydrogenor an aliphatic group; however, Q shall be an aliphatic group in atleast one instance. The term aliphatic chain includes alkyl chains,alkenyl chains, and alkynyl chains, where alkyl, alkenyl, and alkynylare defined above.

The phrase “optionally substituted” is used interchangeably with thephrase “substituted or unsubstituted.” As described herein, compounds ofthe invention can optionally be substituted with one or moresubstituents, such as are illustrated generally above, or as exemplifiedby particular classes, subclasses, and species of the invention. Asdescribed herein, the variables R₁, R₂, R′₂, R₃, R₄, and other variablescontained in the Formulae described herein encompass specific groups,such as alkyl and aryl. Unless otherwise noted, each of the specificgroups for the variables R₁, R₂, R′₂, R₃, R₄, and other variablescontained therein can be optionally substituted with one or moresubstituents described herein. Each substituent of a specific group isfurther optionally substituted with one to three of halo, cyano, oxo,alkoxy, hydroxy, amino, nitro, aryl, cycloaliphatic,heterocycloaliphatic, heteroaryl, haloalkyl, and alkyl. For instance, analkyl group can be substituted with alkylsulfanyl and the alkylsulfanylcan be optionally substituted with one to three of halo, cyano, oxo,alkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl. As anadditional example, the cycloalkyl portion of a(cycloalkyl)carbonylamino can be optionally substituted with one tothree of halo, cyano, alkoxy, hydroxy, nitro, haloalkyl, and alkyl. Whentwo alkoxy groups are bound to the same atom or adjacent atoms, the twoalkxoy groups can form a ring together with the atom(s) to which theyare bound.

In general, the term “substituted,” whether preceded by the term“optionally” or not, refers to the replacement of hydrogen radicals in agiven structure with the radical of a specified substituent. Specificsubstituents are described above in the definitions and below in thedescription of compounds and examples thereof. Unless otherwiseindicated, an optionally substituted group can have a substituent ateach substitutable position of the group, and when more than oneposition in any given structure can be substituted with more than onesubstituent selected from a specified group, the substituent can beeither the same or different at every position. A ring substituent, suchas a heterocycloalkyl, can be bound to another ring, such as acycloalkyl, to form a spiro-bicyclic ring system, e.g., both rings shareone common atom. As one of ordinary skill in the art will recognize,combinations of substituents envisioned by this invention are thosecombinations that result in the formation of stable or chemicallyfeasible compounds.

The phrase “stable or chemically feasible,” as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and preferablytheir recovery, purification, and use for one or more of the purposesdisclosed herein. In some embodiments, a stable compound or chemicallyfeasible compound is one that is not substantially altered when kept ata temperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week.

As used herein, an “effective amount” is defined as the amount requiredto confer a therapeutic effect on the treated patient, and is typicallydetermined based on age, surface area, weight, and condition of thepatient. The interrelationship of dosages for animals and humans (basedon milligrams per meter squared of body surface) is described byFreireich et al., Cancer Chemother. Rep., 50: 219 (1966). Body surfacearea may be approximately determined from height and weight of thepatient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley,N.Y., 537 (1970). As used herein, “patient” refers to a mammal,including a human.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present compounds arewithin the scope of the invention. Unless otherwise stated, alltautomeric forms of the compounds of the invention are within the scopeof the invention. Additionally, unless otherwise stated, structuresdepicted herein are also meant to include compounds that differ only inthe presence of one or more isotopically enriched atoms. For example,compounds having the present structures except for the replacement ofhydrogen by deuterium or tritium, or the replacement of a carbon by a¹³C- or ¹⁴C-enriched carbon are within the scope of this invention. Suchcompounds are useful, for example, as analytical tools or probes inbiological assays, or as therapeutic agents.

Chemical structures and nomenclature are derived from ChemDraw, version11.0.1, Cambridge, Mass.

II. COMMONLY USED ABBREVIATIONS

The following abbreviations are used:

-   -   PG protecting group    -   LG leaving group    -   DCM dichloromethane    -   Ac acetyl    -   DMF dimethylformamide    -   EtOAc ethyl acetate    -   DMSO dimethyl sulfoxide    -   MeCN acetonitrile    -   TCA trichloroacetic acid    -   ATP adenosine triphosphate    -   EtOH ethanol    -   Ph phenyl    -   Me methyl    -   Et ethyl    -   Bu butyl    -   DEAD diethylazodicarboxylate    -   HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid    -   BSA bovine serum albumin    -   DTT dithiothreitol    -   MOPS 4-morpholinepropanesulfonic acid    -   NMR nuclear magnetic resonance    -   HPLC high performance liquid chromatography    -   LCMS liquid chromatography-mass spectrometry    -   TLC thin layer chromatography    -   Rt retention time    -   HOBt hydroxybenzotriazole    -   Ms mesyl    -   Ts tosyl    -   Tf triflyl    -   Bs besyl    -   Ns nosyl    -   Cbz carboxybenzyl    -   Moz p-methoxybenzyl carbonyl    -   Boc tert-butyloxycarbonyl    -   Fmoc 9-fluorenylmethyloxycarbonyl    -   Bz benzoly    -   Bn benzyl    -   PMB p-methoxybenzyl    -   DMPM 3,4-dimethoxybenzyl    -   PMP p-methoxyphenyl

III. METHODS OF SYNTHESIZING COMPOUNDS OF FORMULA I

One aspect of the present invention provides a novel synthesis forgenerating thiazolidine compounds that are useful for the treatment ofmetabolic disorders. One aspect of the present invention provides anovel synthesis for generating thiazolidine compounds that are usefulfor the treatment of metabolic disorders. This synthesis is useful forpreparing a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein each of R₁ and R₃is independently selected from H, halo, aliphatic, and alkoxy, whereinthe aliphatic or alkoxy is optionally substituted with 1-3 of halo; eachof R′₂ and R₂ are independently selected from —H, halo, hydroxy, oroptionally substituted aliphatic, alkoxy, —O-acyl, —O-aroyl,—O-heteroaroyl, —O(SO₂)NH₂, —O—CH(R_(m))OC(O)R_(n),—O—CH(R_(m))OP(O)(OR_(n))₂—O—P(O)(OR_(n))₂, or

wherein each R_(m) is independently C₁₋₆ alkyl, each R_(n) isindependently C₁₋₁₂ alkyl, C₃₋₈ cycloalkyl, or phenyl, each of which isoptionally substituted; R₂ and R′₂ together form oxo, R₂ and R′₂together form —O(CH₂)_(n)O—, wherein n is 2 or 3, or R₂ and R′₂ togetherform —S(CH₂)_(m)S—, wherein m is 2 or 3; and ring A is phenyl,pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, each of which is optionallysubstituted; comprising the step of reacting a compound of Formula 2A:

wherein X is a leaving group, with a compound of Formula 3A

wherein ring B is selected from

wherein Y₁ is hydrogen or PG_(N), wherein PG_(N) is a nitrogenprotecting group, and Y₂ is PG_(O), wherein PG_(O) is an oxygenprotecting group, to form a compound of Formula 4A; and

when Y₁ is other than hydrogen or when Y₂ is present, deprotecting thecompound of Formula 4A to form a compound of Formula I.

It is noted that when ring B is

and Y₁ is other than hydrogen, the nitrogen atom is considered to beprotected, i.e., not of the form

Also, when ring B is

and Y₂ is present, the oxygen atom is considered to be protected. Ineither case where the nitrogen atom or the oxygen atom is protected, thecompound of Formula 4A must undergo an additional deprotection step(e.g., treatment with a reagent (e.g., an aqueous acid or an aqueousbase)) to form a compound of Formula I. However, when Y₁ is hydrogen onring B, then the compound of Formula 4A is a compound of Formula I.

In several embodiments, X is a leaving group selected from —Br, —Cl, —I,—OMs, —OTs, —OTf, —OBs, —ONs, —O-tresylate, or —OPO(OR₄)₂, wherein eachR₄ is independently C₁₋₄ alkyl or two of R₄ together with the oxygen andphosphorous atoms to which they are attached form a 5-7 membered ring.For instance X is a halo. In other instances, X is —Br, —Cl, or —I.

Some embodiments further comprise converting a compound of Formula 2B

into a compound of Formula 2A.

Some embodiments comprise reacting a compound of Formula 5A

wherein X₁ is halo, with a compound of Formula 6A

wherein each of R₅ and R′₅ are independently selected from optionallysubstituted C₁₋₆ alkyl, or R₅ and R′₅ taken together with the nitrogenatom to which they are attached form an optionally substituted 3-7membered monocyclic heterocyle optionally comprising 1-2 additionalheteroatoms selected from N, O, or S, to generate a compound of Formula2B.

Other embodiments comprise halogenating a compound of Formula 7A

to form a compound of Formula 5A.

In many embodiments, the compound of Formula 6A includes a standardWeinreb amide or NCH₃OCH₃. In some embodiments, R₅ and R′₅ takentogether with the nitrogen atom to which they are attached form a ringselected from

In other instances, R₅ and R′₅ taken together with the nitrogen atom towhich they are attached form a ring selected from

And, in some instances, R₅ and R′₅ taken together with the nitrogen atomto which they are attached form

In some embodiments, the compound of Formula 7A comprises

wherein each of R₁ and R₃ is independently selected from H, halo,aliphatic, and alkoxy, wherein the aliphatic or alkoxy is optionallysubstituted with 1-3 of halo; and the compound of Formula 5A comprises

wherein X₁ is halo. For example, the compound of Formula 7A comprises

and the compound of Formula 5A comprises

wherein X₁ is halo.

In some embodiments, the compound of Formula 5A is treated with aGrignard reagent and reacted with compound of Formula 6A to form acompound of Formula 2B. And, in some examples, the Grignard reagentcomprises i-PrMgBr or i-PrMgCl.

In other embodiments, a compound of Formula 7A is reacted with acompound of Formula 6A, under direct acylation conditions, to form acompound of Formula 2B. For example, a compound of Formula 7A is treatedwith n-butyllithium and Me₂NCH₂CH₂OLi, followed by treatment with acompound of Formula 6A to form a compound of Formula 2B.

In some embodiments, X and X₁ are independently selected from —Br and—Cl.

Other embodiments comprise halogenating a compound of Formula 8A

to form a compound of Formula 2A.

In some embodiments, the compound of Formula 8A comprises

wherein each of R₁ and R₃ is independently selected from H, halo,aliphatic, and alkoxy, wherein the aliphatic or alkoxy is optionallysubstituted with 1-3 of halo; each of R′₂ and R₂ are independentlyselected from —H, halo, hydroxy, or optionally substituted aliphatic,alkoxy, —O-acyl, —O-aroyl, —O-heteroaroyl, —O(SO₂)NH₂,—O—CH(R_(m))OC(O)R_(n), —O—CH(R_(m))OP(O)(OR_(n))₂—O—P(O)(OR_(n))₂,

wherein each R₁ is independently C₁₋₆ alkyl, each R_(n) is independentlyC₁₋₁₂ alkyl, C₃₋₈ cycloalkyl, or phenyl, each of which is optionallysubstituted; R₂ and R′₂ together form oxo, R₂ and R′₂ together form—O(CH₂)_(n)O—, wherein n is 2 or 3, or R₂ and R′₂ together form—S(CH₂)_(m)S—, wherein m is 2 or 3.

In some embodiments, each of R₂ and R′₂ is independently selected from—H, —OH, or optionally substituted alkoxy; or R₂ and R′₂ together formoxo, R₂ and R′₂ together form —O(CH₂)_(n)O—, wherein n is 2 or 3, or R₂and R′₂ together form —S(CH₂)_(m)S—, wherein m is 2 or 3. For example,in some instances, R₂ and R′₂ together form oxo.

In some embodiments, the compound of Formula 8A comprises

wherein R₁ is selected from a C₁₋₆ alkyl or C₁₋₆ alkoxy, either of whichis optionally substituted with 1-3 halo, and R₃ is —H or halo. In someexamples of this embodiment, R₁ is a C₁₋₆ alkoxy optionally substitutedwith 1-3 halo. For example, R₁ is selected from methoxy, ethoxy, orpropoxy, any of which is optionally substituted with 1-3 halo.

Some embodiments comprise reacting the compound

with a compound of Formula 9A

wherein ring B is

under condensation conditions to form a compound of Formula 10A, and

hydrogenating the compound of Formula 10A to form a compound of Formula3A.

In some embodiments, ring B of Formula 9A is

Y₁ is PG_(N), and PG_(N) is a nitrogen protecting group selected fromCbz, Moz, Boc, Fmoc, Ac, Bz, Bn, PMB, DMPM, PMP, or trityl. In otherembodiments, ring B of Formula 9A is

and Y₁ is hydrogen.

In some embodiments, ring B of Formula 9A is

Y₂ is PG_(O), and PG_(O) is an oxygen protecting group selected from—Si(R₆)₃, optionally substituted alkyl, or optionally substitutedalkylcarbonyl, wherein each R₆ is independently straight or branchedC₁₋₄ alkyl or phenyl. For example, ring B of Formula 9A is

Y₂ is PG_(O), and PG_(O) is —Si(R₆)₃, wherein each R₆ is independentlyselected from methyl, ethyl, propyl, iso-propyl, tert-butyl, or phenyl.In other examples, ring B of Formula 9A is

Y₂ is PG_(O), and PG_(O) is a C₁₋₆ alkyl or a C₁₋₆ alkylcarbonyl.

In several embodiments, R′₂ and R₂, in any of the Formulae above, areindependently selected from —OMe, —OEt or other optionally substitutedO—C₁₋₆ alkyl groups. In other embodiments, R′₂ and R₂ are groups thatcan readily be converted to oxo without performing an oxidationreaction.

In some embodiments, X is a leaving group that allows for nucleophilicdisplacement by 1,3-thiazolidine-2,4-dione or protected1,3-thiazolidine-2,4-dione. For example, X is —Br, —Cl, —I, —OMs, —OTs,—ONs, or —OPO(OR₄)₂, wherein each R₄ is independently C₁₋₁₂ alkyl, C₃₋₈cycloalkyl, or phenyl, each of which is optionally substituted.

In some embodiments where Y₁ is PG_(N), in any of the Formulae above,PG_(N) is Ac, methoxymethyl, ethoxyethyl, ethoxymethyl, p-methoxybenxyl,methoxycarbonyl, ethoxycarbonyl, or triphenylmethyl.

Another aspect of the present invention provides a process for preparinga compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein ach of R₁ and R₃is independently selected from H, halo, aliphatic, and alkoxy, whereinthe aliphatic or alkoxy is optionally substituted with 1-3 of halo; eachof R′₂ and R₂ are independently selected from —H, halo, hydroxy, oroptionally substituted aliphatic, alkoxy, —O-acyl, —O-aroyl,—O-heteroaroyl, —O(SO₂)NH₂, —O—CH(R_(m))OC(O)R_(n),—O—CH(R_(m))OP(O)(OR_(n))₂—O—P(O)(OR_(n))₂, or

wherein each R_(m) is independently C₁₋₆ alkyl, each R_(n) isindependently C₁₋₁₂ alkyl, C₃₋₈ cycloalkyl, or phenyl, each of which isoptionally substituted; R₂ and R′₂ together form oxo, R₂ and R′₂together form —O(CH₂)_(n)O—, wherein n is 2 or 3, or R₂ and R′₂ togetherform —S(CH₂)_(m)S—, wherein m is 2 or 3; and ring A is phenyl,pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, each of which is optionallysubstituted; comprising the step of reacting a compound of Formula 2A:

wherein X is a leaving group, with a compound of Formula 10A

wherein ring B is selected from

wherein Y₁ is hydrogen or PG_(N), wherein PG_(N) is a nitrogenprotecting group, and Y₂ is PG_(O), wherein PG_(O) is an oxygenprotecting group, to form a compound of Formula 4B; and

hydrogenating the compound of Formula 4B to generate a compound ofFormula 4A, and

when Y₁ is other than hydrogen or when Y₂ is present, deprotecting thecompound of Formula 4A to form a compound of Formula I.

In several embodiments, X is a leaving group selected from —Br, —Cl, —I,—OMs, —OTs, —OTf, —OBs, —ONs, —O-tresylate, or —OPO(OR₄)₂, wherein eachR₄ is independently C₁₋₄ alkyl or two of R₄ together with the oxygen andphosphorous atoms to which they are attached form a 5-7 membered ring.

Some embodiments comprise converting a compound of Formula 2B

into a compound of Formula 2A.

Other embodiments comprising reacting a compound of Formula SA

wherein X₁ is halo, with a compound of Formula 6A

wherein each of R₅ and R′₅ are independently selected from optionallysubstituted C₁₋₆ alkyl, or R₅ and R′₅ taken together with the nitrogenatom to which they are attached form a an optionally substituted 3-7membered monocyclic heterocyle optionally comprising 1-2 additionalheteroatoms selected from N, O, or S to generate a compound of Formula2B.

Some embodiments comprise halogenating a compound of Formula 7A

to form a compound of Formula 5A.

In some embodiments, R₅ and R′₅ taken together with the nitrogen atom towhich they are attached form a ring selected from

For instance, R₅ and R′₅ taken together with the nitrogen atom to whichthey are attached form

In some embodiments, the compound of Formula 7A comprises

wherein each of R₁ and R₃ is independently selected from H, halo,aliphatic, and alkoxy, wherein the aliphatic or alkoxy is optionallysubstituted with 1-3 of halo; and the compound of Formula 5A comprises

wherein X₁ is halo. For example, the compound of Formula 7A comprises

and the compound of Formula 5A comprises

wherein X₁ is halo.

In other embodiments, the compound of Formula 5A is treated with aGrignard reagent and reacted with compound of Formula 6A to form acompound of Formula 2B. And, in some examples, the Grignard reagentcomprises i-PrMgBr.

In some embodiments, X and X₁ are independently selected from —Br and—Cl.

Other embodiments comprise reacting a compound a compound of Formula 7A

with a compound of Formula 6A

wherein each of R₅ and R′₅ are independently selected from optionallysubstituted C₁₋₆ alkyl, or R₅ and R′₅ taken together with the nitrogenatom to which they are attached form a an optionally substituted 3-7membered monocyclic heterocyle optionally comprising 1-2 additionalheteroatoms selected from N, O, or S, under direct acylation conditions,to generate a compound of Formula 2B.

Some embodiments comprise halogenating a compound of Formula 8A

to form a compound of Formula 2A.

And, some embodiments the compound of Formula 8A comprises

wherein each of R₁ and R₃ is independently selected from H, halo,aliphatic, and alkoxy, wherein the aliphatic or alkoxy is optionallysubstituted with 1-3 of halo; each of R′₂ and R₂ are independentlyselected from —H, halo, hydroxy, or optionally substituted aliphatic,alkoxy, —O-acyl, —O-aroyl, —O-heteroaroyl, —O(SO₂)NH₂,—O—CH(R_(m))OC(O)R_(n), —O—CH(R_(m))OP(O)(OR_(n))₂, —O—P(O)(OR_(n))₂,

wherein each R_(m) is independently C₁₋₆ alkyl, each R_(n) isindependently C₁₋₁₂ alkyl, C₃₋₈ cycloalkyl, or phenyl, each of which isoptionally substituted;

R₂ and R′₂ together form oxo,

R₂ and R′₂ together form —O(CH₂)_(n)O—, wherein n is 2 or 3, or

R₂ and R′₂ together form —S(CH₂)_(m)S—, wherein m is 2 or 3.

In some embodiments, each of R₂ and R′₂ is independently selected from—H, —OH, or optionally substituted alkoxy; or R₂ and R′₂ together formoxo, R₂ and R′₂ together form —O(CH₂)_(n)O—, wherein n is 2 or 3, or R₂and R′₂ together form —S(CH₂)_(m)S—, wherein m is 2 or 3. For example,R₂ and R′₂ together form oxo.

In some embodiments, the compound of Formula 8A comprises

wherein R₁ is selected from a C₁₋₆ alkyl or C₁₋₆ alkoxy, either of whichis optionally substituted with 1-3 halo, and R₃ is —H or halo. In someexamples, R₁ is a C₁₋₆ alkoxy optionally substituted with 1-3 halo. Inother examples, R₁ is selected from methoxy, ethoxy, or propoxy, any ofwhich is optionally substituted with 1-3 halo.

Some embodiments comprise reacting the compound

with a compound of Formula 9A

wherein ring B is

under condensation conditions to form a compound of Formula 10A. In someinstances, ring B of Formula 9A is

Y₁ is PG_(N), and PG_(N) is a nitrogen protecting group selected fromCbz, Moz, Boc, Fmoc, Ac, Bz, Bn, PMB, DMPM, trityl, or PMP. In otherinstances, ring B of Formula 9A is

and Y₁ is hydrogen. In other instances, ring B of Formula 9A is

Y₂ is PG_(O), and PG_(O) is an oxygen protecting group selected from—Si(R₆)₃, optionally substituted alkyl, or optionally substitutedalkylcarbonyl, wherein each R₆ is independently straight or branchedC₁₋₄ alkyl or phenyl. Or, ring B of Formula 9A is

Y₂ is PG_(O), and PG_(O) is —Si(R₆)₃, wherein each R₆ is independentlyselected from methyl, ethyl, propyl, iso-propyl, tert-butyl, or phenyl.

Alternatively, ring B of Formula 9A is

Y₂ is PG_(O), and PG_(O) is a C₁₋₆ alkyl or a C₁₋₆ alkylcarbonyl.

IV. EXEMPLARY SYNTHESES

The following synthetic schemes represent example embodiments of thepresent invention:

wherein X and Y₁ are defined in Formula I, above.

In several embodiments, starting material is generated according toScheme 1A, below:

wherein X is a leaving group, as defined above in Formula I.

In several embodiments, the starting material is generated according toScheme 1B, below:

wherein X is —Cl.

In several embodiments, the starting material ib is generated accordingto Scheme 1C, below:

wherein Y₁ is hydrogen.

wherein X and Y₁ are defined above in Formula I.

In some embodiments, starting material iia is generated according toScheme 2A, below:

wherein X is —Cl.

V. NOVEL COMPOUNDS

Another aspect of the present invention provides novel compounds thatare useful in the synthesis of compounds of Formula I. For example, oneaspect of the present invention provides a compound of Formula 11A, 12A,or 13A

wherein R₇ is a C₁₋₆ alkyl optionally substituted with 1-3 halo.

For example, in some embodiments, the compound is one selected from

Another aspect of the present invention provides a compound of Formulaib

wherein Y¹ is defined above in Formula I.

Another aspect of the present invention provides a compound selectedfrom

V. EXAMPLES Example 1 Preparation of5-{4-[2-(3-methoxyphenyl)-2-oxoethoxy]benzyl}-1,3-thiazolidine-2,4-dione

To a stirring solution of 5-(4-hydroxybenzyl)thiazolidine-2,4-dione (100mg, 0.4 mmol) in DMSO (2 ml), potassium tert-butoxide (106 mg, 0.941mmol) was added. Stirring continued at RT for about 1 hour.2-Bromo-3′-methoxyacetophenone (100 mg, 0.5 mmol) was then added to themixture. After 2 hours, LCMS showed that the reaction was complete. Thereaction mixture was partitioned between EtOAc and water, and theaqueous phase was extracted with EtOAc. Combined extracts were washedwith brine, dried on (Na₂SO₄), filtered, and evaporated in vacuo. Theresidue was analyzed on a small RediSep column eluting with 0-10%acetone/DCM. Fractions containing the product were combined andevaporated in vacuo to afford 70 mg of5-{4-[2-(3-methoxyphenyl)-2-oxoethoxy]benzyl}-1,3-thiazolidine-2,4-dioneas a pale yellow solid.

Test Results Physical Appearance Pale yellow solid. ¹H NMR Spectrum δ12.03 (s, 1H), 7.62 (d, J = 7.67 Hz, 1H), (400 MHz, DMSO-d4 7.49 (m,2H), 7.27 (dd, J = 8.19, 2.54 Hz, 1H), 7.15 (d, J = 8.71 Hz, 2H), 6.91(d, J = 8.5 Hz, 2H), 5.55 (s, 2H), 4.88 (dd, J = 9.12, 4.35 Hz, 1H),3.83 (s, 3H), 3.31 (m, 1H), 3.05 (dd, J = 14.1, 9.33 Hz, 1H). HPLCAnalysis Retention time: 3.760 min, 96% at 210 and 99% at 254 nm.Agilent 1100 HPLC Agilent Scalar C18 150 × 4.6 mm 5 micron columnSolvent A - Water (0.1% TFA) Solvent B - Acetonitrile (0.07% TFA)Gradient - 10 min 95% A to 95% B; 5 min hold; then recycle UV Detection@ 210 and 254 nm. Mass Spectrum Consistent: ES+ 372.0 m/z (M + 1) andES− 370.0 m/z (M − 1). Melting Point 183-184° C.

Example 2 Preparation of2-(4-(hydroxymethyl)phenoxy)-1-(3-methoxyphenyl)ethanone

To a stirring solution of 2-bromo-3′-methoxyacetophenone (3.00 g, 13.1mmol; Supplier=Kalexsyn; Lot=803-TTP-145) in acetone (30 ml) was added4-hydroxybenzylalcohol (1.69 g, 13.6 mmol) and potassium carbonate (1.88g, 13.6 mmol). The resulting mixture was stirred at RT overnight. Thereaction mixture was partitioned between water and EtOAc, and theaqueous phase was extracted with EtOAc. The combined organic phases werewashed with brine, dried (Na₂SO₄), filtered and evaporated in vacuo. Theproduct was analyzed on a large Biotage column eluting with 50%EtOAc/hexanes. Fractions containing product were combined and evaporatedin vacuo to give 2.98 g of the title compound as a white solid.

Test Results Physical Appearance White solid. ¹H NMR Spectrum δ 7.58 (d,J = 7.7 Hz, 1H), 7.53 (m, 1H), 7.42 (400 MHz, CDCl₃) (t, J = 7.9 Hz,1H), 7.29 (m, 2H), 7.17 (dd, J = 8.3, 1.7 Hz, 1H), 6.93 (d, J = 8.7 Hz,2H), 5.28 (s, 2H), 4.62 (s, 2H), 3.87 (s, 3H). HPLC Analysis Retentiontime: 3.339 min, 100% at 210 and 254 nm. Agilent 1100 HPLC AgilentScalar C18 150 × 4.6 mm 5 micron column Solvent A - Water (0.1% TFA)Solvent B - Acetonitrile (0.07% TFA) Gradient - 10 min 95% A to 95% B; 5min hold; then recycle UV Detection @ 210 and 254 nm. Mass SpectrumConsistent: ES+ 273.04 m/z (M + 1).

Example 3 Assays

Assays for Measuring Reduced PPARγ Receptor Activation

Whereas activation of the PPARγ receptor is generally believed to be aselection criteria to select for molecules that may have anti-diabeticand insulin sensitizing pharmacology, this invention finds thatactivation of this receptor should be a negative selection criterion.Molecules will be chosen from this chemical space because they havereduced, not just selective, activation of PPARγ. The optimal compoundshave at least a 10-fold reduced potency as compared to pioglitazone andless than 50% of the full activation produced by rosiglitazone in assaysconducted in vitro for transactivation of the PPARγ receptor. The assaysare conducted by first evaluation of the direct interactions of themolecules with the ligand binding domain of PPARγ. This can be performedwith a commercial interaction kit that measures the direct interactionby florescence using rosiglitazone as a positive control. Further assayscan be conducted in a manner similar to that described by Lehmann et al.[Lehmann J M, Moore L B, Smith-Oliver T A: An AntidiabeticThiazolidinedione is a High Affinity Ligand for PeroxisomeProliferator-activated Receptor (PPAR) J. Biol. Chem. (1995) 270: 12953]but will use luciferase as a reporter as in Vosper et al. [Vosper, H.,Khoudoli, G A, Palmer, C N (2003) The peroxisome proliferators activatedreceptor d is required for the differentiation of THP-1 moncytic cellsby phorbol ester. Nuclear Receptor 1:9]. Compound stocks will bedissolved in DMSO and added to the cell cultures at final concentrationsof 0.1 to 100 μM and the relative activation will be calculated asinduction of the reporter gene (luciferase) as corrected for by theexpression of the control plasmid (coding for galactosidase).Pioglitazone and rosiglitazone will be used as reference compounds asdescribed above.

In addition to showing the reduced activation of the PPARγ receptor invitro, the compounds will not produce significant activation of thereceptor in animals. Compounds dosed to full effect for insulinsensitizing actions in vivo (see below) will be not increase activationof PPARγ in the liver as measured by the expression of a P2, a biomarkerfor ectopic adipogenesis in the liver [Matsusue K, Haluzik M, Lambert G,Yim S-H, Oksana Gavrilova O, Ward J M, Brewer B, Reitman M L, Gonzalez FJ. (2003) Liver-specific disruption of PPAR in leptin-deficient miceimproves fatty liver but aggravates diabetic phenotypes. J. Clin.Invest.; 111: 737] in contrast to pioglitazone and rosiglitazone, whichdo increase a P2 expression under these conditions.

The insulin sensitizing and antidiabetic pharmacology are measured inthe KKA^(Y) mice as previously reported [Hofmann, C., Lornez, K., andColca, J. R. (1991). Glucose transport deficiency corrected by treatmentwith the oral anti-hyperglycemic agent Pioglitazone. Endocrinology,129:1915-1925.] Compounds are formulated in 1% sodium carboxymethylcellulose, and 0.01% tween 20 and dosed daily by oral gavage.After 4 days of once daily treatment, treatment blood samples are takenfrom the retro-orbital sinus and analyzed for glucose, triglycerides,and insulin as described in Hofmann et al. Doses of compounds thatproduce at least 80% of the maximum lowering of glucose, triglycerides,and insulin will not significantly increase the expression of a P2 inthe liver of these mice.

Measuring PPARγ Receptor Activation

The ability of several exemplary compounds of the present invention tobind to PPARγ was measured using a commercial binding assay (InvitrogenCorporation, Carlsbad, Calif.) that measures the test compounds abilityto bind with PPAR-LBD/Fluormone PPAR Green complex. These assays wereperformed on three occasions with each assay using four separate wells(quadruplicate) at each concentration of tested compound. The data aremean and SEM of the values obtained from the three experiments.Rosiglitazone was used as the positive control in each experiment.Compounds were added at the concentrations shown, which range from0.1-100 micromolar.

Glucose, Insulin, and Triglyceride in Diabetic KKAy Mice Treated withExemplary Compounds of the Present Invention.

The insulin sensitizing and antidiabetic pharmacology are measured inthe KKA^(Y) mice as previously reported [Hofmann, C., Lornez, K., andColca, J. R. (1991). Glucose transport deficiency corrected by treatmentwith the oral anti-hyperglycemic agent Pioglitazone. Endocrinology,129:1915-1925.]. Compounds are formulated in 1% sodium carboxymethylcellulose, and 0.01% tween 20 and dosed daily by oral gavage.After 4 days of once daily treatment, blood samples are taken from theretro-orbital sinus and analyzed for glucose, triglycerides, and insulinas described in Hofmann et al. Doses of compounds that produce at least80% of the maximum lowering of glucose, triglycerides, and insulin willnot significantly increase the expression of a P2 in the liver of thesemice.

Compounds were formulated by suspension and orally dosed to KKA^(Y) miceat 93 mg/kg for 4 days. The compounds were first dissolved in DMSO andthen placed into aqueous suspension containing 7-10% DMSO, 1% sodiummethylcarboxycellulose, and 0.01% Tween 20. On the fifth day, the micewere fasted and blood samples were obtained approximately 18 hours afterthe last dose. The parameters were measured by standard assay methods.Data are mean and SEM N=6-12 mice.

TABLE A Assay Results Cmpd Glucose Insulin TG Example Description No.(Mean/SD) (Mean/SD) (Mean/SD) Glucose Vehicle A 518 24 284  59  5  365-[4-(2-oxo-2- phenylethoxy)benzyl]-1,3- thiazolidine-2,4-dione  

1 0.71 0.03 0.13 0.02 0.56 0.05 36.5  2.4 5-{4-[2-(4-fluorophenyl)-2-oxoethoxy]benzyl}-1,3- thiazolidine-2,4-dione  

2 0.61 0.02 0.10 0.02 0.45 0.02 63.7 12.2 5-{4-[2-(2-fluorophenyl)-2-oxoethoxy]benzyl}-1,3- thiazolidine-2,4-dione  

3 0.64 0.02 0.20 0.07 0.62 0.04 97.9  4.0 5-{4-[2-(3-fluorophenyl)-2-oxoethoxy]benzyl}-1,3- thiazolidine-2,4-dione  

4 0.62 0.05 0.24 0.05 0.46 0.07 64.8 17.5 5-{4-[2-(3-methoxyphenyl)-2-oxoethoxy]benzyl}-1,3- thiazolidine-2,4-dione  

5 0.56 0.05 0.22 0.03 0.41 0.06 13.2  0.6 5-{4-[2-(2-methoxyphenyl)-2-oxoethoxy]benzyl)-1,3- thiazolidine-2,4-dione  

6 0.75 0.04 1.20 0.27 0.80 0.11 76.2  5.6 5-{4-[2-(3-chlorophenyl)-2-oxoethoxy]benzyl}-1,3- thiazolidine-2,4-dione  

7 0.54 0.03 0.59 0.33 0.43 0.04 74.4  1.4 5-{4-[2-(2-chlorophenyl)-2-oxoethoxy]benzyl}-1,3- thiazolidine-2,4-dione  

8 1.05 0.03 0.47 0.04 0.97 0.10 — 5-{4-[2-(4-methoxyphenyl)-2-oxoethoxy]benzyl}-1,3- thiazolidine-2,4-dione  

9 1.00 0.03 0.76 0.21 0.90 0.06 37.2  5.0

Compound Nos. 1-5 exhibited a plasma insulin level of less than about 5ng/ml and compound no. 6 exhibited a plasma insulin level between about15 and 20 ng/ml; compound nos. 1, 2, 3, 4, and 5 exhibited a plasmatriglyceride level of between about 100 and 200 mg/dl, and compound no.6 exhibited a plasma triglyceride level between about 300 and 400 mg/dl;compound nos. 1, 2, 3, 4, and 5 exhibited a plasma glucose level ofbetween about 350 and 425 mg/dl and compound no. 6 exhibited a plasmaglucose level between about 450 and 525 mg/dl.

The PPARγ-sparing compounds of this invention will be more effective forthe treatment of diseases caused by metabolic inflammation such asdiabetes and metabolic syndrome by limiting the side effectsattributable to direct and partial activation of nuclear transcriptionfactors.

Because the compounds of the present invention exhibit reduced PPARγactivation, it is anticipated that these compounds are suitable for usein combination with other compounds having antidiabetic activity, suchas metformin, DDP-4 inhibitors, or other antidiabetic agents thatfunction by differing mechanisms to augment the actions or secretions ofGLP1 or insulin. Specifically because of the reduced PPARγ interaction,these compounds will also be useful for treating dyslipidemia associatedwith metabolic inflammatory diseases combining particularly well withlipid lowering statins such as atorvastatin or the like. It is alsoanticipated that the combination of a compound of Formula I and otherantidiabetic compounds will be more effective in treating diabetes thancombinations with PPAR-activating compounds as they will avoid sideeffects associated with PPARγ activation that may include volumeexpansion, edema, and bone loss.

Other Embodiments

It is to be understood that while the invention has been described inconjunction with the detailed description thereof, the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are within the scope of thefollowing claims.

1. A process for preparing a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein Each of R₁ and R₃is independently selected from H, halo, aliphatic, and alkoxy, whereinthe aliphatic or alkoxy is optionally substituted with 1-3 of halo; Eachof R′₂ and R₂ are independently selected from —H, halo, hydroxy, oroptionally substituted aliphatic, alkoxy, —O-acyl, —O-aroyl,—O-heteroaroyl, —O(SO₂)NH₂, —O—CH(R_(m))OC(O)R_(n),—O—CH(R_(m))OP(O)(OR_(n))₂—O—P(O)(OR_(n))₂, or

wherein each R_(m) is independently C₁₋₈ alkyl, each R_(n) isindependently C₁₋₁₂ alkyl, C₃₋₈ cycloalkyl, or phenyl, each of which isoptionally substituted; R₂ and R′₂ together form oxo, R₂ and R′₂together form —O(CH₂)_(n)O—, wherein n is 2 or 3, or R₂ and R′₂ togetherform —S(CH₂)_(m)S—, wherein m is 2 or 3; and Ring A is phenyl,pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, each of which is optionallysubstituted; comprising the step of: reacting a compound of Formula 2A:

wherein X is a leaving group, with a compound of Formula 3A

wherein ring B is selected from

wherein Y₁ is hydrogen or PG_(N), wherein PG_(N) is a nitrogenprotecting group, and Y₂ is PG_(O), wherein PG_(O) is an oxygenprotecting group, to form a compound of Formula 4A; and

when Y₁ is other than hydrogen or when Y₂ is present, deprotecting thecompound of Formula 4A to form a compound of Formula I.
 2. The processof claim 1, wherein X is a leaving group selected from —Br, —Cl, —I,—OMs, —OTs, —OTf, —OBs, —ONs, —O-tresylate, or —OPO(OR₄)₂, wherein eachR₄ is independently C₁₋₄ alkyl or two of R₄ together with the oxygen andphosphorous atoms to which they are attached form a 5-7 membered ring.3. The process of claim 2, further comprising converting a compound ofFormula 2B

into a compound of Formula 2A.
 4. The process of claim 3, furthercomprising reacting a compound of Formula 5A

wherein X₁ is halo, with a compound of Formula 6A

wherein each of R₅ and R′₅ are independently selected from optionallysubstituted C₁₋₆ alkyl, or R₅ and R′₅ taken together with the nitrogenatom to which they are attached form a an optionally substituted 3-7membered monocyclic heterocycle optionally comprising 1-2 additionalheteroatoms selected from N, O, or S to generate a compound of Formula2B.
 5. The process of claim 4, further comprising halogenating acompound of Formula 7A

to form a compound of Formula 5A.
 6. The process of claim 4, wherein R₅and R′₅ taken together with the nitrogen atom to which they are attachedform a ring selected from


7. (canceled)
 8. The process of claim 5, wherein the compound of Formula7A comprises

wherein each of R₁ and R₃ is independently selected from H, halo,aliphatic, and alkoxy, wherein the aliphatic or alkoxy is optionallysubstituted with 1-3 of halo; and the compound of Formula 5A comprises

wherein X₁ is halo.
 9. The process of claim 8, wherein the compound ofFormula 7A comprises

and the compound of Formula 5A comprises

wherein X₁ is halo.
 10. The process of claim 4, wherein the compound ofFormula 5A is treated with a Grignard reagent and reacted with compoundof Formula 6A to form a compound of Formula 2B.
 11. The process of claim10, wherein the Grignard reagent comprises i-PrMgBr.
 12. The process ofclaim 4, wherein X and X₁ are independently selected from —Br and —Cl.13. The process of claim 3, further comprising reacting a compound acompound of Formula 7A

with a compound of Formula 6A

wherein each of R₅ and R′₅ are independently selected from optionallysubstituted C₁₋₆ alkyl, or R₅ and R′₅ taken together with the nitrogenatom to which they are attached form a an optionally substituted 3-7membered monocyclic heterocyle optionally comprising 1-2 additionalheteroatoms selected from N, O, or S, under direct acylation conditions,to generate a compound of Formula 2B.
 14. The process of claim 1,further comprising halogenating a compound of Formula 8A

to form a compound of Formula 2A.
 15. The process of claim 14, whereinthe compound of Formula 8A comprises

wherein each of R₁ and R₃ is independently selected from H, halo,aliphatic, and alkoxy, wherein the aliphatic or alkoxy is optionallysubstituted with 1-3 of halo; each of R′₂ and R₂ are independentlyselected from —H, halo, hydroxy, or optionally substituted aliphatic,alkoxy, —O-acyl, —O-aroyl, —O-heteroaroyl, —O(SO₂)NH₂,—O—CH(R_(m))OC(O)R_(n), —O—CH(R_(m))OP(O)(OR_(n))₂, —O—P(O)(OR_(n))₂,

wherein each R_(m) is independently C₁₋₆ alkyl, each R_(n) isindependently C₁₋₁₂ alkyl, C₃₋₈ cycloalkyl, or phenyl, each of which isoptionally substituted; R₂ and R′₂ together form oxo, R₂ and R′₂together form —O(CH₂)_(n)O—, wherein n is 2 or 3, or R₂ and R′₂ togetherform —S(CH₂)_(m)S—, wherein m is 2 or
 3. 16. The process of claim 14,wherein each of R₂ and R′₂ is independently selected from —H, —OH, oroptionally substituted alkoxy; or R₂ and R′₂ together form oxo, R₂ andR′₂ together form —O(CH₂)_(n)O—, wherein n is 2 or 3, or R₂ and R′₂together form —S(CH₂)_(m)S—, wherein m is 2 or
 3. 17. The process ofclaim 16, wherein R₂ and R′₂ together form oxo.
 18. The process of claim14, wherein the compound of Formula 2A comprises

wherein R₁ is selected from a C₁₋₆ alkyl or C₁₋₆ alkoxy, either of whichis optionally substituted with 1-3 halo, and R₃ is —H or halo.
 19. Theprocess of claim 18, wherein R₁ is a C₁₋₆ alkoxy optionally substitutedwith 1-3 halo.
 20. The process of claim 19, wherein R₁ is selected frommethoxy, ethoxy, or propoxy, any of which is optionally substituted with1-3 halo.
 21. The process of claim 1, further comprising reacting thecompound

with a compound of Formula 9A

wherein ring B is

under condensation conditions to form a compound of Formula 10A, and

hydrogenating the compound of Formula 10A to form a compound of Formula3A.
 22. The process of claim 21, wherein ring B of Formula 9A is

Y₁ is PG_(N), and PG_(N) is a nitrogen protecting group selected fromCbz, Moz, Boc, Fmoc, Ac, Bz, Bn, PMB, DMPM, trityl, or PMP.
 23. Theprocess of claim 21, wherein ring B of Formula 9A is

and Y₁ is hydrogen.
 24. The process of claim 21, wherein ring B ofFormula 9A is

Y₂ is PG_(O), and PG_(O) is an oxygen protecting group selected from—Si(R₆)₃, optionally substituted alkyl, or optionally substitutedalkylcarbonyl, wherein each R₆ is independently straight or branchedC₁₋₄ alkyl or phenyl.
 25. The process of claim 24, wherein ring B ofFormula 9A is

Y₂ is PG_(O), and PG_(O) is —Si(R₆)₃, PG_(O) is a C₁₋₆ alkyl, or PG_(O)is a C₁₋₆ alkylcarbonyl, wherein each R₆ is independently selected frommethyl, ethyl, propyl, iso-propyl, Pert-butyl, or phenyl.
 26. (canceled)27. A compound of Formula 11A, 12A, or 13A

wherein R₇ is a C₁₋₆ alkyl optionally substituted with 1-3 halo.
 28. Acompound selected from


29. A compound of Formula ib

wherein Y¹ is hydrogen or PG_(N), wherein PG_(N) is a nitrogenprotecting group.
 30. A compound selected from


31. A process for preparing a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein Each of R₁ and R₃is independently selected from H, halo, aliphatic, and alkoxy, whereinthe aliphatic or alkoxy is optionally substituted with 1-3 of halo; Eachof R′₂ and R₂ are independently selected from —H, halo, hydroxy, oroptionally substituted aliphatic, alkoxy, —O-acyl, —O-aroyl,—O-heteroaroyl, —O(SO₂)NH₂, —O—CH(R_(m))OC(O)R_(n),—O—CH(R_(m))OP(O)(OR_(n))₂—O—P(O)(OR_(n))₂,

wherein each R_(m) is independently C₁₋₆ alkyl, each R_(n) isindependently C₁₋₁₂ alkyl, C₃₋₈ cycloalkyl, or phenyl, each of which isoptionally substituted; R₂ and R′₂ together form oxo, R₂ and R′₂together form —O(CH₂)_(n)O—, wherein n is 2 or 3, or R₂ and R′₂ togetherform —S(CH₂)_(m)S—, wherein m is 2 or 3; and Ring A is phenyl,pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, each of which is optionallysubstituted; comprising the step of: reacting a compound of Formula 2A:

wherein X is a leaving group, with a compound of Formula 10A

wherein ring B is selected from

wherein Y₁ is hydrogen or PG_(N), wherein PG_(N) is a nitrogenprotecting group, and Y₂ is PG_(O), wherein PG_(O) is an oxygenprotecting group, to form a compound of Formula 4B; and

hydrogenating the compound of Formula 4B to generate a compound ofFormula 4A, and

when Y₁ is other than hydrogen or when Y₂ is present, deprotecting thecompound of Formula 4A to form a compound of Formula I.
 32. The processof claim 31, wherein X is a leaving group selected from —Br, —Cl, —I,—OMs, —OTs, —OTf, —OBs, —ONs, —O-tresylate, or —OPO(OR₄)₂, wherein eachR₄ is independently C₁₋₄ alkyl or two of R₄ together with the oxygen andphosphorous atoms to which they are attached form a 5-7 membered ring.33. The process of claim 32, further comprising converting a compound ofFormula 2B

into a compound of Formula 2A.
 34. The process of claim 33, furthercomprising reacting a compound of Formula 5A

wherein X₁ is halo, with a compound of Formula 6A

wherein each of R₅ and R′₅ are independently selected from optionallysubstituted C₁₋₆ alkyl, or R₅ and R′₅ taken together with the nitrogenatom to which they are attached form a an optionally substituted 3-7membered monocyclic heterocycle optionally comprising 1-2 additionalheteroatoms selected from N, O, or S to generate a compound of Formula2B.
 35. The process of claim 34, further comprising halogenating acompound of Formula 7A

to form a compound of Formula 5A.
 36. The process of claim 34, whereinR₅ and R′₅ taken together with the nitrogen atom to which they areattached form a ring selected from


37. (canceled)
 38. The process of claim 35, wherein the compound ofFormula 7A comprises

wherein each of R₁ and R₃ is independently selected from H, halo,aliphatic, and alkoxy, wherein the aliphatic or alkoxy is optionallysubstituted with 1-3 of halo; and the compound of Formula 5A comprises

wherein X₁ is halo.
 39. The process of claim 38, wherein the compound ofFormula 7A comprises

and the compound of Formula 5A comprises

wherein X₁ is halo.
 40. The process of claim 34, wherein the compound ofFormula 5A is treated with a Grignard reagent and reacted with compoundof Formula 6A to form a compound of Formula 2B.
 41. The process of claim40, wherein the Grignard reagent comprises i-PrMgBr.
 42. The process ofclaim 34, wherein X and X₁ are independently selected from —Br and —Cl.43. The process of claim 33, further comprising reacting a compound acompound of Formula 7A

with a compound of Formula 6A

wherein each of R₅ and R′₅ are independently selected from optionallysubstituted C₁₋₆ alkyl, or R₅ and R′₅ taken together with the nitrogenatom to which they are attached form a an optionally substituted 3-7membered monocyclic heterocyle optionally comprising 1-2 additionalheteroatoms selected from N, O, or S, under direct acylation conditions,to generate a compound of Formula 2B.
 44. The process of claim 31,further comprising halogenating a compound of Formula 8A

to form a compound of Formula 2A.
 45. The process of claim 44, whereinthe compound of Formula 8A comprises

wherein each of R₁ and R₃ is independently selected from H, halo,aliphatic, and alkoxy, wherein the aliphatic or alkoxy is optionallysubstituted with 1-3 of halo; each of R′₂ and R₂ are independentlyselected from —H, halo, hydroxy, or optionally substituted aliphatic,alkoxy, —O-acyl, —O-aroyl, —O-heteroaroyl, —O(SO₂)NH₂,—O—CH(R_(m))OC(O)R_(n), —O—CH(R_(m))OP(O)(OR_(n))₂, —O—P(O)(OR_(n))₂,

wherein each R_(m) is independently C₁₋₆ alkyl, each R_(n) isindependently C₁₋₁₂ alkyl, C₃₋₈ cycloalkyl, or phenyl, each of which isoptionally substituted; R₂ and R′₂ together form oxo, R₂ and R′₂together form —O(CH₂)_(n)O—, wherein n is 2 or 3, or R₂ and R′₂ togetherform —S(CH₂)_(m)S—, wherein m is 2 or
 3. 46. The process of claim 44,wherein each of R₂ and R′₂ is independently selected from —H, —OH, oroptionally substituted alkoxy; or R₂ and R′₂ together form oxo, R₂ andR′₂ together form —O(CH₂)_(n)O—, wherein n is 2 or 3, or R₂ and R′₂together form —S(CH₂)_(m)S—, wherein m is 2 or
 3. 47. The process ofclaim 46, wherein R₂ and R′₂ together form oxo.
 48. The process of claim44, wherein the compound of Formula 8A comprises

wherein R₁ is selected from a C₁₋₆ alkyl or C₁₋₆ alkoxy, either of whichis optionally substituted with 1-3 halo, and R₃ is —H or halo.
 49. Theprocess of claim 48, wherein R₁ is a C₁₋₆ alkoxy optionally substitutedwith 1-3 halo.
 50. The process of claim 49, wherein R₁ is selected frommethoxy, ethoxy, or propoxy, any of which is optionally substituted with1-3 halo.
 51. The process of claim 31, further comprising reacting thecompound

with a compound of Formula 9A

wherein ring B is

under condensation conditions to form a compound of Formula 10A.
 52. Theprocess of claim 51, wherein ring B of Formula 9A is

Y₁ is PG_(N), and PG_(N) is a nitrogen protecting group selected fromCbz, Moz, Boc, Fmoc, Ac, Bz, Bn, PMB, DMPM, trityl, or PMP.
 53. Theprocess of claim 51, wherein ring B of Formula 9A is

and Y₁ is hydrogen.
 54. The process of claim 51, wherein ring B ofFormula 9A is

Y₂ is PG_(O), and PG_(O) is an oxygen protecting group selected from—Si(R₆)₃, optionally substituted alkyl, or optionally substitutedalkylcarbonyl, wherein each R₆ is independently straight or branchedC₁₋₄ alkyl or phenyl.
 55. The process of claim 54, wherein ring B ofFormula 9A is

Y₂ is PG_(O), and PG_(O) is —Si(R₆)₃, PG_(O) is a C₁₋₆ alkyl, or PG_(O)is a C₁₋₆ alkylcarbonyl, wherein each R₆ is independently selected frommethyl, ethyl, propyl, iso-propyl, tert-butyl, or phenyl.
 56. (canceled)